Research Summary
Neuroendocrine control of pituitary function. Hypothalamic regulation of energy homeostasis.

Research Activities
The Central Melanocortin System and the Regulation of Energy BalanceThe long-term objective of this project is to understand how the brain senses levels of peripheral energy stores and integrates these signals to maintain energy balance. This project focuses on the melanocortin neuropeptide system which plays a key role in regulating appetite and body weight and is an important target for leptin and insulin in the hypothalamus. Studies center on the regulation of proopiomelanocortin (POMC) and the POMC-derived peptides, α-MSH, γ-MSH and ß-EP, together with agouti related protein (AgRP) which is synthesized in the hypothalamus and is a potent antagonist of the MSH peptides. Transgenic and knockout mouse models are being used to study role of the melanocortin system in modulating metabolic responses to energy excess on a high fat diet and to food restriction and to characterize underlying mechanisms with respect to changes in body weight/composition and glucose and fat metabolism with a focus on energy expenditure and fuel oxidation. An important focus is on the regulation pf POMC peptide processing with respect to energy balance. These studies are highly relevant to human energy balance as mutations in POMC, POMC processing enzymes and in melanocortin receptors have all been associated with human obesity and there are many parallels with rodent models of melanocortin deficiency.

Cerebrospinal Fluid Neuropeptide, Hormonal and Metabolomic Analysis in Human Energy BalanceThis project focuses on cerebrospinal fluid (CSF) POMC and AgRP measurements as a surrogate for hypothalamic melanocortin activity, as related to CSF leptin, insulin and nutrient levels. Recent studies in the rodent show that levels of the intact POMC prohormone in CSF reflect hypothalamic POMC activity. We have confirmed that the POMC prohormone is the predominant POMC peptide in human CSF and are examining the relationship of CSF POMC to BMI and adiposity. An important goal is to identify biomarkers in CSF that could predict responses to dieting and to pharmacotherapy for obesity that target the melanocortin system.

New Approaches to the Diagnosis of Cushing’s DiseaseNew assays are being evaluated that will improve the differential diagnosis of ACTH-dependent Cushing’s syndrome based on tumor specific differences in the processing of ACTH and its precursor, proopiomelanocortin (POMC). This is being evaluated in conjunction with petrosal sinus sampling in order to develop a less invasive way to distinguish between pituitary and ectopic sources of ACTH secretion.

Committees and Society Memberships
Diplomate, American Board of Internal Medicine Diplomate, Subspecialty Board of Endocrinology and Metabolism The Endocrine Society Pituitary Society The Obesity Society American Association for the Advancement of Science